There is an unmet need to inhibit the key cancer promoting transcription factor MYC. MYC (both cMYC and MYCN) acts downstream of many cell receptor complexes and signal transduction pathways to activate genes that drive cancer cell growth and proliferation. To date, small molecule inhibitors of MYC have been elusive. An innovative approach would be to indirectly orthogonally diminish the activity of MYC by enhancing its degradation using PI-3 kinase (PI-3K) inhibitors combined with blocking transcription of the gene producing MYC using inhibitors of the bromodomain protein BRD4. While small molecule inhibitors or PI-3K and BRD4 are individually used in cancer clinical trials, none has made it through development to FDA approval. Although combination treatments are common in cancer, there is an unmet need for every increasing combinations to inhibit multiple targets to maximize efficacy. This becomes unfeasible due to prohibitive costs when combining expensive targeted therapies in addition to being a barrier to early clinical evaluation of such complex combinations of drugs. While exploring a novel PI-3K inhibitor scaffold, thienopyranone (TP) scaffold based on a chromone derivative we discovered that these compounds also can potently inhibit BRD4 (preliminary results). The chromone backbone is common to the inhibition of BOTH targets thus providing the opportunity to now explore the newly found BRD4 activity while maintaining potent PI-3K activity (overall objective). Consolidating the inhibition of PI-3K AND BRD4 to maximally inhibit MYC activity with one molecule would fill all the unmet needs stated above. This proposal will evaluate this approach by achieving the following aims setting the stage for phase II efforts to optimize the expected dual inhibitor lead compound(s) to a clinical candidate: Aim (Task) #1. Determine structure activity relationship (SAR) for TP compounds for BRD4 inhibition. Approach: Synthesize 30 TP compounds and determine their BRD4 and PI-3K inhibition profiles. Aim (Task) #2. Develop predictive computational BRD4 model for the in silico docking of designed compounds. Approach: Vary the molecular in silico fit parameters of the BRD4 model until docking predictions of a TP dataset correlates with actual BRD4 assay binding results creating a validated docking model. Aim (Task) #3. Determine effects on MYC and therapeutic index for dual BRD4/PI-3K inhibition. Approach: Determine MYC expression and activity levels and compare toxicity towards cancer cell lines versus normal cell lines when exposed to single BRD4 or PI-3K versus dual BRD4/PI-3K inhibition conditions. The contribution of this research is it provides an effective mechanism to block MYC activity that drives cancer and will be significant because it will allow enhanced combination treatments of MYC dependent cancers, such as CLL, medulloblastoma, and neuroblastoma. This approach is innovative because it attacks a key cancer target using two orthogonal mechanisms with a single compound and it challenges the cost-ignoring efficacy-limiting mentality of one-drug one-target prevalent in cancer research in an area with no FDA approved treatments.